tbuckley/cabot-search huggingface dataset:
Comparison of prognostic reliability of TNM staging systems version 7/8 and SARCULATOR in primary localized liposarcomas of the extremity or trunk wall.
Authors: Hanna Kosela-Paterczyk, Pawel Teterycz, Anna Mariuk-Jarema, Michal Wagrodzki, Marcin Zdzienicki, Piotr Rutkowski
Journal: Journal of Clinical Oncology (2022)

e23529 Background: The oncological staging system should provide meaningful information regarding the patients’ prognosis. For soft tissue sarcomas, available staging systems include AJCC version 8, AJCC version 7, and nomogram-based approaches such as SARCULATOR (which additionally includes age and subtype). This work compares these systems using a group of extremity/trunk wall cases of liposarcoma (LPS). Methods: We have included all (N = 147) consecutive, newly diagnosed LPS patients treated in our institution between 2010 and 2021. We have excluded atypical lipomatous tumors. Patients’ and tumor characteristics were collected, and AJCC staging and SARCULATOR risk assessment were performed. Appropriate Cox proportional hazard models were fitted. The results were compared using the concordance index, Akaike information criterion (AIC), and partial likelihood ratio (PLR) test for non-nested Cox models. Results: In this group, 81 (55.1%) patients were male; the mean age in the group was 54 years (SD:16). Most tumors (83%) were localized on the lower extremity, with 8.8% on the upper extremity and 8.2% on the trunk. 66% of cases were myxoid LPS, 17.7% - dedifferentiated and 16.3% - pleomorphic. The median tumor size was 12 cm (IQR 9 – 18). Patients’ prognostic groups are summarized in Table. The median follow-up was 43 months (95%CI:38-51). The median overall survival (OS) was not reached. The 5-year survival rate was 68% (95%CI:62-75). The concordance for AJCC version 7, AJCC version 8, and SARCULATOR were respectively 0.625, 0.705, and 0.778. The AIC in the same order were: 311, 301, 274. The PLR test showed that AJCC version 8 fits better than AJCC version 7 (p for superiority = 0.036) while SARCULATOR fits better than AJCC version 8 (p for superiority = 0.028). Conclusions: New staging systems improve in better predicting patients outcome. In rare diseases such as sarcomas, it is crucial to have access to more personalized nomograms such as SARCULATOR.[Table: see text]
Developmental toxicity and programming alterations of multiple organs in offspring induced by medication during pregnancy
Authors: Zhengjie Lu, Yu Guo, Dan Xu, Hao Xiao, Yongguo Dai, Kexin Liu, Liaobin Chen, Hui Wang
Journal: Acta Pharmaceutica Sinica B (2022)

Medication during pregnancy is widespread, but there are few reports on its fetal safety. Recent studies suggest that medication during pregnancy can affect fetal morphological and functional development through multiple pathways, multiple organs, and multiple targets. Its mechanisms involve direct ways such as oxidative stress, epigenetic modification, and metabolic activation, and it may also be indirectly caused by placental dysfunction. Further studies have found that medication during pregnancy may also indirectly lead to multi-organ developmental programming, functional homeostasis changes, and susceptibility to related diseases in offspring by inducing fetal intrauterine exposure to too high or too low levels of maternal-derived glucocorticoids. The organ developmental toxicity and programming alterations caused by medication during pregnancy may also have gender differences and multi-generational genetic effects mediated by abnormal epigenetic modification. Combined with the latest research results of our laboratory, this paper reviews the latest research progress on the developmental toxicity and functional programming alterations of multiple organs in offspring induced by medication during pregnancy, which can provide a theoretical and experimental basis for rational medication during pregnancy and effective prevention and treatment of drug-related multiple fetal-originated diseases.
Racial disparities in the screening mammography continuum within a diverse healthcare system.
Authors: Anisha Ganguly, Kelsey K. Baker, Mary Weber Redman, Adelaide McClintock, Rachel Lynn Yung
Journal: Journal of Clinical Oncology (2022)

e18580 Background: Racial disparities in breast cancer have been extensively characterized in the literature. Access to screening mammography is a significant contributor to breast cancer disparities. Decreased access to mammography translates into disparities in breast cancer through delayed presentation to care. The USPSTF recommends biannual screening mammography of women 50-74 with average risk for breast cancer. Methods: We conducted a cross-sectional analysis of encounter-level data for Black and white female primary care patients aged 50-74 in the University of Washington Medicine system who were due for mammogram in 2019. Completion of steps of the mammography continuum (referral, scheduling, and completion of mammogram) were compared among Black and white women. Multivariable logistic regression was used to explore race and mammogram completion, adjusting for age, language, referral, insurance, clinical site, wellness visit utilization, and history of prior mammogram. Results: The study population comprised 18,156 women of whom 2,059 (11.3%) were Black and 16,097 (88.7%) were white. Among Black women, 26.8% were referred to screening mammogram, 12.9% self-referred, 39.3% were scheduled, and 21.4% completed their mammogram, compared to 21.1%, 20.6%, 41.4%, and 26.9% among white women respectively. The greatest attrition among Black women was in the step of completing a mammogram after it was scheduled, which was higher seen in white women at the same step. Adjusted analyses demonstrated an association between Black race and lower rates of screening mammography completion (OR 0.85, [95% CI 0.78-0.98], p = 0.02). Conclusions: Our analysis assessed racial disparities in steps of the screening mammography continuum in a large, diverse health system. Black race was associated with lower screening mammography completion after adjustment for several covariates. Provider-initiated referral was higher for Black women, while self-referral was higher for white women. Both Black and white women experienced highest attrition from no-show rates for scheduled mammograms, though attrition was greater for Black women. These findings have systems implications for future interventions, such as patient navigators or system-driven nudges, to mitigate disparities in breast cancer screening. [Table: see text]
Can we reduce unnecessary Trans-Urethral Resection of a Bladder Tumours (TURBT)? A Dutch nationwide study in benign histology after primary TURBT
Authors: J.W. Van Hattum, H.E.O. Quainoo, J.E. Freund, J.R. Oddens, T.M. De Reijke
Journal: European Urology (2022)
Sabizabulin has both cytotoxic and cytostatic activity in Phase 1b/2 clinical of men with metastatic castration resistant prostate cancer who progressed on androgen receptor targeting agents
Authors: M. Markowski, M. Eisenberger, C. Pieczonka, R.H. Getzenberg, D. Rodriguez, K.G. Barnette, M.S. Steiner, D. Saltzstein, E. Antonarakis, R. Tutrone
Journal: European Urology (2022)
Pulsed vs. continuous TFLEP: A multi-institution trial to compare intra and early post-operative outcomes
Authors: M. Maltagliati, L. Berti, U. Besana, C. Buizza, S. Micali, B. Rocco, M.C. Sighinolfi, A. Pacchetti, J.B. Roche, G. Bozzini
Journal: European Urology (2022)
Role of target biopsy, perilesional biopsy, and random biopsy in the detection of clinically significant prostate cancer by mpMRI-guided transrectal ultrasound fusion biopsy during active surveillance protocol
Authors: G. Novara, G. Zecchini, S. Spagna, A. Taverna, G. Aiello, A. Lauro, C.S. Lacognata, M.P. Gardiman, A. Calpista, L. Ruggera, A. Morlacco, F. Dal Moro
Journal: European Urology (2022)
Results of the safety run-in of gedatolisib plus talazoparib in advanced triple negative or BRCA 1/2 positive HER2 negative breast cancer.
Authors: Sneha Deepak Phadke, Menggang Yu, Kathy Miller, Ami N. Shah, Oana Cristina Danciu, Kari Braun Wisinski
Journal: Journal of Clinical Oncology (2022)

e13075 Background: Metastatic triple negative breast cancer (TNBC) is a disease subtype with a poor prognosis, though advancements have been made in the use of targeted therapies, such as poly (ADP-ribose) polymerase inhibitors (PARPi) for those with germline BRCA 1/2 mutations. Up to 2/3 of TNBC tumors have acquired defects in homologous recombination (HR) DNA repair, yet PARPi monotherapy has been ineffective in extending survival in these patients. Phosphoinositide-3-kinase (PI3K)/mTOR pathway alterations are also common, and preclinical data supports that PI3K/mTOR inhibition may disrupt normal function of the HR complex and increase dependency on PARP enzymes for HR DNA repair. Thus, combining a PI3K/mTORi with a PARPi may result in a synergistic anti-neoplastic effect. Methods: The safety run-in portion of this study evaluated the safety and preliminary efficacy of the combination of weekly IV gedatolisib (PI3K/mTORi) and continuous daily talazoparib. Germline BRCA mutations were not required. The safety run-in was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). A 3+3 design was utilized for dose escalation, with starting dose at level 1. Dose levels are as shown in the Table. Eligibility criteria included patients ≥ age 18 who had received 1-3 prior lines of therapy for advanced TNBC or advanced HER2-negative BC with a germline BRCA 1/2 mutation. Those with untreated CNS metastasis were excluded as were those type I diabetes or uncontrolled type II diabetes, due to the risk of hyperglycemia with gedatolisib. Results: A total of 14 female patients were enrolled on to the safety run-in phase of the trial. Median age was 53 (range 30-67). Most patients (79%) were Caucasian, 14% were African American, and 7% unknown. The most common adverse events (AEs) of any grade were fatigue, anemia, nausea, and oral mucositis. Grade 1 hyperglycemia was noted in about 1/3 of the cohort, with 1 grade 3 event. There were 3 patients who experienced grade 4 AEs, thrombocytopenia (2) and lymphopenia (1). There was 1 DLT of grade 3 neutropenia which occurred at dose level 1. The MTD of gedatolisib was 180 mg and MTD of talazoparib was 1 mg. In this preliminary cohort, 3 patients achieved PR and 5 patients achieved SD. Median duration of PR was 13.34 months and median duration of SD was 4.11 months. Of the 3 patients with a BRCA 1 or 2 mutation, 2 had a best response of PR and the other SD. Conclusions: The safety run-in indicated that this combination is safe and well tolerated with mostly grade 1-2 AEs. This combination therapy has moved into the phase II trial, with 2 cohorts. Cohort A includes BRCA-wildtype patients with TNBC and cohort 2 includes those with a BRCA mutation and HER2-negative disease. Clinical trial information: NCT03911973. [Table: see text]
Association between lung immune prognostic index, microbiome, and immunotherapy outcomes in non–small cell lung cancer.
Authors: Edouard Auclin, Alexis Nolin-Lapalme, Corentin Richard, Julie Malo, Marion Tonneau, Myriam Benlaifaoui, Mayra Ponce, Meriem Messaoudene, Yusuke Okuma, Taiki Hakozaki, Bertrand Routy
Journal: Journal of Clinical Oncology (2022)

9050 Background: Host-related inflammatory biomarkers and gut microbiome are two major prognostic factors for non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (ICI). In this study, we aimed to assess an association between the Lung Immune Prognostic Index (LIPI) and the microbiome composition on ICI outcomes in two independent cohorts of NSCLC pts. Methods: We included 205 patients with advanced NSCLC treated with ICI (monotherapy or in combination with chemotherapy) from two independent cohorts. Metagenomics microbiome profiling was performed on the Canadian discovery cohort of 72 pts while 16S rRNA microbiome sequencing was used in the Japanese validation cohort of 133 pts. The LIPI score was calculated using the dNLR (neutrophils/[leucocytes-neutrophils]) and lactate deshydrogenase (LDH). Pts were classified as Good (G: 0 high factor), Intermediate (I: 1 high factor) and Poor (P: 2 high factors). Median overall survival (OS) was estimated using the Kaplan-Meier method. Microbiome diversity indexes and bacterial relative abundances were compared according to LIPI groups. Results: Among the 72 pts included in the discovery cohort, the median follow-up of 20.6 months (mos). The LIPI was distributed as follows: G (n = 31, 43.1%), I (31, 43.1%), P (10, 13.8%) and baseline characteristics were well balanced between the 3 groups. When segregating pts according to LIPI, the OS was 25.6 mo, 19.8 mo, and 5.7 mo in the G, I (HR: 1.71, 95%CI: 0.80-3.65) and P (HR: 3.97, 95%CI: 1.60-9.82) groups, respectively (p = 0.003). The microbiome alpha diversity was lower in the P group compared with the G group (p = 0.03), and there was a trend towards different microbiome composition in beta diversity (p = 0.055) between both groups. Pts in the G group had a favorable microbiome (enriched in Ruminococcus and Anaerostipes), while pts from the P group had an unfavorable microbiome (enriched in Enterobacteriaceae and Clostridium symbiosum and lavalense). Next, in the validation cohort of 133 pts, LIPI was distributed as follows: G (n = 62, 46.6%), I (51, 38.3%), P (20, 15%). Pts with G LIPI had not reached their median OS compared to pts in the I [15.7 mo HR: 1.60 (0.88-2.94)] and P [8.8 mo groups, HR: 2.02 (0.98-4.19)], p = 0.03. Similar to the discovery cohort, at the genus level, G LIPI group had enrichment of Ruminococcus as well as Anaerostipes compared with pts in the P and I groups with an overrepresentation of Hungatella. Conclusions: Host-related inflammatory biomarkers, represented by the LIPI, seemed to be associated with microbiome and ICI outcomes in pts treated with NSCLC. This observation was validated in an external validation cohort. This link could be in relation to the presence of proinflammatory bacteria in pts with poor LIPI.
Does a positive multi-parametric MRI always warrant prostate biopsy? The importance of integrating clinical and imaging data based on a large, multi-institutional series
Authors: A. Stabile, G. Gandaglia, E. Mazzone, F. Barletta, S. Scuderi, D. Robesti, G.O. Cirulli, D. Cannoletta, F. Pellegrino, L. Nocera, G. Sorce, M. De Angelis, C.A. Bravi, A. Martini, T. Seisen, M. Roupret, J.R. Karnes, N. Fossati, F. De Cobelli, A. Esposito, G. Brembilla, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.
Authors: Tianshu Liu, Mudan Yang, Jin Li, Yueyin Pan, Ying Yuan, Shanyong Yi, Junsheng Wang, Ying Cheng, Jifeng Feng, Shegan Gao, Xicheng Wang, Song Qu, Xizhi Zhang, Jin Lu, Peng Xiu, Shuni Wang, Xinfeng Yang, Jia Fan
Journal: Journal of Clinical Oncology (2022)

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]
Phase 1 first-in-human trial of MTB-9655, the first oral inhibitor of ACSS2, in patients with advanced solid tumors.
Authors: Ruth Perets, Ravit Geva, Meredith McKean, Andreas Goutopoulos, Omri Erez, Monica Phadnis, Hagop Youssoufian, Brian E. Schwartz, Vikram Kansra, Ali Fattaey
Journal: Journal of Clinical Oncology (2022)

e20609 Background: ACSS2 catalyzes the ligation of acetate with Co-enzyme A to generate Acetyl-CoA. Selection to an acetate dependent state has been demonstrated and is associated with the induction of ACSS2 gene expression in certain human cancers. The ACSS2 gene is amplified in human breast cancers, and its expression is up-regulated in human colorectal, breast, ovarian and lung cancers. MTB-9655 is a potent (IC 50 = 0.15nM in biochemical, and EC 50 = 3nM in cellular assays) oral inhibitor of ACSS2 and induces anti-tumor effects in xenograft mouse models of human colorectal, breast and lung cancers that express high levels of ACSS2. Methods: Using a combined accelerated (single patient for the first two dose levels) and 3+3 dose escalation and dose expansion design, MTB-9655 was administered on a once daily (QD) schedule in 21-day cycles in a Phase 1 trial to assess safety, tolerability, PK and potential anti-tumor activity in patients with advanced solid tumors. Re-staging was performed every 2 cycles. Results: To-date, 10 subjects have received MTB-9655 at doses up to 225mg. MTB-9655 was absorbed rapidly post oral dosing with a half-life of 6-12 hours. Dose proportional exposure was observed on day 1 of the first dosing cycle, and steady-state exposure was noted between day 8 and day 1 of the second dosing cycle. Dose limiting toxicities or Grade 3 treatment-related adverse events (AEs) have not been observed up to the 225mg dose level. The most common AE was nausea (29%). Low grade increase in bilirubin levels was observed in 1 patient at 225mg dose, without changes in other liver enzyme levels. Increased bilirubin levels were readily reversed with dose interruption. As MTB-9655 is a 729nM inhibitor of the UGT1A1 enzyme, the increase in bilirubin levels is likely attributed to off-target UGT1A1 inhibitory activity. Conclusions: MTB-9655 has been well tolerated, and the safety profile was predictable based on preclinical studies in rodents and non-human primates. Dose proportional plasma drug levels were observed and predicted to have reached biologically active levels. Expected increase in bilirubin levels was observed in 1 patient, which may be used as a marker of significant drug exposure. MTD has not reached up to the 225mg dose and the dose escalation is continuing. Development of MTB-9655 is planned as a single agent, and based on animal model studies, in combination with standard of care platinum-based agents and gemcitabine. Clinical trial information: NCT04990739.
Small molecule SMU-CX24 targeting toll-like receptor 3 counteracts inflammation: A novel approach to atherosclerosis therapy
Authors: Xiaohong Cen, Baoqu Wang, Yuqing Liang, Yanlin Chen, Yu Xiao, Shaohua Du, Kutty Selva Nandakumar, Hang Yin, Shuwen Liu, Kui Cheng
Journal: Acta Pharmaceutica Sinica B (2022)

Toll-like receptor 3 (TLR3), as an important pattern recognition receptor (PRR), dominates the innate and adaptive immunity regulating many acute and chronic inflammatory diseases. Atherosclerosis is proved as an inflammatory disease, and inflammatory events involved in the entire process of initiation and deterioration. However, the contribution of TLR3 to atherosclerosis remains unclear. Herein, we identified the clinical relevance of TLR3 upregulation and disease processes in human atherosclerosis. Besides, activation of TLR3 also directly led to significant expression of atherogenic chemokines and adhesion molecules. Conversely, silencing TLR3 inhibited the uptake of oxLDL by macrophages and significantly reduced foam cell formation. Given the aberrance in TLR3 functions on atherosclerosis progression, we hypothesized that TLR3 could serve as novel target for clinical atherosclerosis therapy. Therefore, we developed the novel ellipticine derivative SMU-CX24, which specifically inhibited TLR3 (IC
Assessing the safety of transperineal prostate biopsy with only a single dose of amoxicillin/clavulanic acid using the PrecisionPoint™ Transperineal Access System (PPTAS); A retrospective review of 500 cases and technique description
Authors: H. Islam, M. Sheikh, S. Ghiblawi, M. Abuismaeil, A. Farooq
Journal: European Urology (2022)